title: Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations.
abstract: BACKGROUND
  Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics.
  
  
  OBJECTIVE
  The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products.
  
  
  METHODS
  Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs.
  
  
  RESULTS
  The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types.
  
  
  CONCLUSIONS
  Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another.
  
  
  CONCLUSIONS
  Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient's status from seizure-free to refractory.
authors.affiliation: Laboratory of Biopharmaceutics & Pharmacokinetics, Faculty of Pharmacy, National & Kapodistrian University of Athens, 15771, Athens, Greece.
authors.forename: Vangelis
authors.initials: V
authors.lastname: Karalis
authors.forename: Panos
authors.initials: P
authors.lastname: Macheras
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D017277:Drug Approval; D057915:Drug Substitution; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D009010:Monte Carlo Method; D013810:Therapeutic Equivalency
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D016568:Drugs, Generic